In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially-viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound.
Further, in the manufacture of drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of drug is provided following administration to a patient.
Chemical stability, solid state stability, and “shelf life” of the active ingredients are also very important factors. The drug substance, and compositions containing it, should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
Moreover, it is also important to be able to provide drug in a form which is as chemically pure as possible.
The skilled person will appreciate that, typically, if a drug can be readily obtained in a stable form, such as a stable crystalline form, advantages may be provided, in terms of ease of handling, ease of preparation of suitable pharmaceutical formulations, and a more reliable solubility profile.
International Patent Application No. PCT/SE01/02657 (WO 02/44145, earliest priority date 01 Dec. 2000, filed 30 Nov. 2001, published 06 Jun. 2002) discloses a number of compounds that are, or are metabolised to compounds which are, competitive inhibitors of trypsin-like proteases, such as thrombin. The following three compounds are amongst those that are specifically disclosed:
(a) Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)—(S)Aze-Pab(OMe):
which compound is referred to hereinafter as Compound A;(b) Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)—(S)Aze-Pab(2,6-diF)(OMe):
which compound is referred to hereinafter as Compound B; and(c) Ph(3-Cl)(5-OCH2CH2F)—(R)CH(OH)C(O)—(S)Aze-Pab(OMe):
which compound is referred to hereinafter as Compound C.
Abbreviations are listed at the end of this specification.
The methoxyamidine Compounds A, B and C are metabolised following oral and/or parenteral administration to the corresponding free amidine compounds, which latter compounds have been found to be potent inhibitors of thrombin.
Processes for the synthesis of Compounds A, B and C are described in Examples 12, 40 and 22 (respectively) of International Patent Application No. PCT/SE01/02657.
Specific pharmaceutically-acceptable salts of Compounds A, B and C are not disclosed in PCT/SE01/02657. Further, no information is provided in relation to how crystalline forms of Compounds A, B or C, and particularly salts thereof, may be prepared.